Excessive GABA Produced by Brain Astrocytes Impedes Subcortical Stroke Recovery

by | Sep 8, 2020 | 2020, Brain Health, Gaba, Stroke

Written by Joyce Smith, BS. This study suggests that the inhibition of MAO-B, an enzyme encoded by the MAO-B gene, supports the recovery of subcortical stroke when combined with a rehabilitation program. 

Brain HealthSubcortical stroke has a poor prognosis 1 and represents 39% of all ischemic stokes in humans 2.  Stroke leads to diaschisis, a loss of function (particularly a reduction in glucose metabolism) 3 in other brain regions connected to the damaged area 4. White matter diseases, including subcortical stroke and vascular dementia 5, Alzheimer’s 6 and Parkinson’s 7 diseases all stimulate astrocyte proliferation and the excessive production of the inhibitory neurotransmitter GABA which in turn leads to cortical hypometabolism and neuronal cell damage. A recent study demonstrated how electrical stimulation of damaged brain areas in combination with rehabilitation significantly reversed diastasis and improved functional recovery compared to rehabilitation alone 8,9; however, the molecular and cellular mechanisms involved in the process were not be clarified.

Nam and colleagues 10 hypothesized that excessive astrocyte production and GABA release affects the activity of neighboring motor neurons and impedes rehabilitation-aided motor functional recovery and that by inhibiting MAO-B (the GABA-synthesizing enzyme), glucose metabolism could be re-established  which would accelerate rehabilitation-aided motor functional recovery. In an animal study the team utilized rat models of three subcortical stroke scenarios to test their theory: rats with sham stroke (control), rats with stroke but without treatment and rats with stroke and treatment.

  • Using 2-deoxy-2-[18F]-fluoro-Dglucose micro-positron emission tomography (FDG-microPET) ( )to examine the brains of the stroked rats, researchers found extensive evidence of glucose hypometabolism that significantly increased the area of damaged brain tissue up to 7 days post stroke, while the sham stroke rats showed no evidence of damaged  brain tissue.
  • MAO-B is one of the key enzymes in the production of GABA and a biomarker of astrocyte activity. Using immunohistochemistry antibodies against GABA and MAO-B, the team found significantly increased immune reactivity of GABA and MAO-B in the astrocytes in the stroke damaged regions of the stroke animals compared to the sham-operated animals.
  • Treating stroke animals with KDS2010 (a drug that reverses MAO-B activity) inhibited the activity of MAO-B and significantly restored GABA and other markers of excessive astrocyte activity, thus reducing the extent and volume of the infarct damage. However, the brain morphology and GABA astrocyte levels of the sham-operated animals treated with KDS2010 were unaffected.
  • Using putrescine injection or adenovirus, researchers found that either could induce the synthesis of excessive astrocyte GABA and recapitulate cortical hypometabolism, lending more credence to their initial hypothesis that over reactive astrocytes and GABA release decreases glucose metabolism.
  • Lastly, researchers found that post stroke motor deficits were dramatically recovered in the sham group (73%) when KDS2010 treatment was combined with a rehabilitation regimen.

Collectively, the data validates the hypothesis that cortical glucose hypometabolism in subcortical stroke is caused by excessive astrocytic GABA activity and MAO-B inhibition that slow functional recovery. Thus reducing cortical hypometabolism through MAO-B inhibition can be a therapeutic target for functional recovery after subcortical stroke. Future clinical trials that further validate the potential therapeutic effect of MAO-B inhibition for post-stroke recovery are warranted.

Source: Nam, Min-Ho, Jongwook Cho, Dae-Hyuk Kwon, Ji-Young Park, Junsung Woo, Jungmoo Lee, Sangwon Lee et al. “Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke.” Cell Reports 32, no. 1 (2020): 107861.

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Posted September 8, 2020.

Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from  the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.

References:

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